tbuckley/cabot-search huggingface dataset:
Abstract P2001: Deficiency Of Claudin-5 Leads To Myocardial Atrophy And Dilation In Mouse Heart With Severe Mitochondrial Dysfunction And Electrical Dissociation
Authors: Tao Luo, Baihe Chen, Haiqiong Liu, Xianbao Wang, Ahmed Abdel-Latif, Jin Kuyng Kim, Masafumi Kitakaze
Journal: Circulation Research (2023)

Background: Cardiac overexpression of Claudin-5 (Cldn5) exerts protection against myocardial ischemia and reperfusion injury. However, whether cardiac deficiency of Cldn5 affects cardiac function is still unclear. Here we investigated the role of Cldn5 in mouse heart by means of cardiac Cldn5 knockdown to better understand the intracellular function of Cldn5 in cardio-protection. Methods and Results: Cldn5 shRNA adeno-associated virus (AAV) was used to knockdown Cldn5 in the left ventricle of male C57BL/6J mice by intramyocardial injection. Four weeks post AAV injection, echocardiography and electrocardiography were performed to measure cardiac function. We found 25% of mice died in Cldn5 shRNA AAV injection group. The residual mice were terminated followed by left ventricles isolation for proteomics analysis, cytokine analysis, WGA staining, Masson-trichrome staining and transmission electron microscope (TEM) observation. The signal pathway markers of apoptosis, autophagy and lipid peroxidation were also detected by western blot. The protein level of Cldn5 in left ventricles was decreased by 75% in shRNA AAV injection group accompanied by changes of bcl-2, bax, LC3II, p62, Cox2 and GPX4. The fraction shortening of the heart was decreased by 23.5% with ventricular dilation and ST elevation. We also observed the increase of IL-1beta, TNF alpha, BNP, CT and cTnI in myocardium. WGA staining showed the area of cross section of single cardiomyocyte was decreased and Masson staining showed the collagen deposition was increased in myocardium. The TEM indicated Cldn5 knockdown induced mitochondrial fission and depletion. Finally, the proteomics analysis demonstrated that Cldn5 knockdown severely disturbed ATP metabolic regulation, mitochondrial permeability transition pore opening, calcium ion transport, cardiac contraction, endoplasmic reticulum stress response and antioxidant activity in the AAV injected myocardium. Conclusion: We demonstrated for the first time the deficiency of Cldn5 in myocardium caused myocardial atrophy and dilation with deteriorative heart function. The mechanism of Cldn5 deficiency-induced cardiac dysfunction is associated with severe mitochondrial dysfunction and excitation-contraction coupling.
Abstract P1133: Bmal1 Drives Postnatal Cardiac Hypertrophy Via Circadian Chromatin Remodeling Of The Pro-hypertrophic Gene Sik1
Authors: Adrian Arrieta, Douglas Chapski, Anna Reese, Manuel Rosa-Garrido, Thomas M Vondriska
Journal: Circulation Research (2023)

Background: Neonatal cardiomyocyte physiological hypertrophy is temporally encoded, yet the chromatin remodeling mechanisms driving this behavior are unclear. In other tissues, genes regulated by the master circadian rhythm factor BMAL1 display circadian oscillations in histone acetylation and nucleosome and RNAPII occupancy. Hypothesis: BMAL1 regulates temporal chromatin remodeling and expression of genes critical to neonatal cardiac hypertrophy. Methods: RNAPII and BMAL1 ChIP-seq and ATAC-seq data were analyzed to identify genes at which BMAL1 may drive chromatin remodeling. Bmal1 was knocked down in neonatal rat ventricular myocytes via siRNA and hypertrophy was assessed by measuring cell size and L-azidohomoalanine incorporation into total protein, and Nppa/Nppb RT-qPCR. Bmal1 target gene promoter accessibility was assessed via MNase-qPCR and levels of chromatin-associated nucleosome core histones H2A, H2B, H3 and H4 were measured by immunoblotting of acid soluble chromatin fractions. Results: RNAPII occupancy at Bmal1 target genes was increased in adult as compared to E12.5 hearts. BMAL1 ChIP-seq and ATAC-seq revealed cardiac-specific BMAL1 co-localization (other tissues served as controls) with accessibility at the pro-hypertrophic gene salt-inducible kinase 1 (Sik1). BMAL1 knockdown impaired serum-stimulated hypertrophy, indicated by 30% decrease in cell size, 50% decrease in L-azidohomoalanine incorporation into total protein, and 80% decrease in Nppa/Nppb mRNA. BMAL1 knockdown decreased mRNA and promoter accessibility of BMAL1 targets Per2 and Sik1 and decreased chromatin-associated histones by 50%. Finally, Sik1 knockdown decreased myocyte size and Nppb mRNA. Conclusion: These findings indicate that BMAL1 controls Sik1 expression—and possibly that of other growth inducing genes—in part by modulating nucleosome assembly at specific loci, thereby regulating neonatal myocyte physiological hypertrophy.
Abstract P1008: Characterizing Complex Tandem Repeat Variants And Their Contribution To Congenital Heart Disease
Authors: Abhilash Suresh, Sarah U Morton, Daniel Quiat, Steven DePalma, Joshua Gorham, Bruce D Gelb, Jonathan G Seidman, Christine E Seidman
Journal: Circulation Research (2023)

Congenital heart disease (CHD) is a major cause of childhood mortality and lifelong morbidity in children and adults. CHD has a strong genetic basis, with exome and short read whole genome sequencing (srWGS) identifying genetic contributions to CHD risk in around 45% of affected individuals, while the remaining 55% have not had a specific genetic risk identified. Variation in tandem repeats (TRs), defined as repeated sequences of base pairs, has been implicated in several diseases and can affect gene expression. TR polymorphism in coding or regulatory regions of CHD related genes can alter function and expression, thereby modifying risk of CHD in patients. Identifying variants in TRs has been a challenge due to multiple variants at each site, as well as difficulty resolving long expansions with short read sequencing technologies. New bioinformatic tools have enabled identification of high-confidence short-TR (STR) variants in srWGS. Additionally, long read whole genome sequencing (lrWGS), with read lengths of 10-20 kilobases, enables genotyping of longer TRs that are missed by srWGS. We hypothesized that patients with CHD will have a higher burden of de novo and transmitted TRs near known CHD genes. We identified de novo and transmitted STR variants near known CHD genes in srWGS data from 1900 CHD proband and their parents in the Pediatric Cardiac Genomics Consortium (PCGC), and 1611 non-CHD probands and their parents. Transmitted STR variants in CHD probands were enriched in 5’-UTR, introns, and promoters of CHD genes compared to non-CHD probands. We identified large de novo repeats near known CHD genes such as NOTCH2 and RBFOX2 . Additionally we used Pacbio HiFi lrWGS on 150 PCGC probands without an established etiology for CHD. Combining these analyses, we identified 3,243 repeat regions with low read depth in srWGS, and therefore unable to be resolved accurately, near known CHD genes and from lrWGS we assess length polymorphisms using Tandem Repeat Finder. TRs that harbor large variation in length were identified within intronic regions of CHD genes including FLT4 , NFATC1 , and PKD1 . We suggest that polymorphic repeat regions provide new candidate variants or altering gene transcription or splicing and thereby contribute to CHD.
Copper ion/gallic acid MOFs-laden adhesive pomelo peel sponge effectively treats biofilm-infected skin wounds and improves healing quality
Authors: Jianqiu Yang, Zhenzhen Huang, Jiang Tan, Jingye Pan, Shixuan Chen, Wenbing Wan
Journal: Bioactive Materials (2023)

Bacterial infection and scar formation remain primary challenges in wound healing. To address these issues, we developed a decellularized pomelo peel (DPP) functionalized with an adhesive PVA-TSPBA hydrogel and antibacterial gallic acid/copper MOFs. The hybrid wound dressing demonstrates favorable biocompatibility. It does not impede the proliferation of fibroblasts or immune cells and can stimulate fibroblast migration, endothelial angiogenesis, and M2 macrophage polarization. Additionally, the dressing can scavenge reactive oxygen species (ROS) and provide antioxidant effects. Furthermore, DPP + MOF@Gel effectively inhibits the viability of S. aureus and E. coli in vitro and in vivo. The histological observations revealed enhanced granulation tissue formation, re-epithelialization, and angiogenesis in the DPP + MOF@Gel group compared to other groups. The local immune response also shifted from a pro-inflammatory to a pro-regenerative status with DPP + MOF@Gel treatment. The skin incision stitching experiment further exhibits DPP + MOF@Gel could reduce scar formation during wound healing. Taken together, the hybrid DPP + MOF@Gel holds great promise for treating bacteria-infected skin wounds and inhibiting scar formation during wound healing.
Integrin α3 promotes T <sub>H</sub> 17 cell polarization and extravasation during autoimmune neuroinflammation
Authors: Eunchong Park, William E. Barclay, Alejandro Barrera, Tzu-Chieh Liao, Harmony R. Salzler, Timothy E. Reddy, Mari L. Shinohara, Maria Ciofani
Journal: Science Immunology (2023)

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) caused by CNS-infiltrating leukocytes, including T H 17 cells that are critical mediators of disease pathogenesis. Although targeting leukocyte trafficking is effective in treating autoimmunity, there are currently no therapeutic interventions that specifically block encephalitogenic T H 17 cell migration. Here, we report integrin α3 as a T H 17 cell–selective determinant of pathogenicity in experimental autoimmune encephalomyelitis. CNS-infiltrating T H 17 cells express high integrin α3, and its deletion in CD4 + T cells or Il17a fate-mapped cells attenuated disease severity. Mechanistically, integrin α3 enhanced the immunological synapse formation to promote the polarization and proliferation of T H 17 cells. Moreover, the transmigration of T H 17 cells into the CNS was dependent on integrin α3, and integrin α3 deficiency enhanced the retention of CD4 + T cells in the perivascular space of the blood-brain barrier. Integrin α3–dependent interactions continuously maintain T H 17 cell identity and effector function. The requirement of integrin α3 in T H 17 cell pathogenicity suggests integrin α3 as a therapeutic target for MS treatment.
IL-31–dependent neurogenic inflammation restrains cutaneous type 2 immune response in allergic dermatitis
Authors: Marlys S. Fassett, Joao M. Braz, Carlos A. Castellanos, Juan J. Salvatierra, Mahsa Sadeghi, Xiaobing Yu, Andrew W. Schroeder, Jaela Caston, Priscila Munoz-Sandoval, Suparna Roy, Steven Lazarevsky, Darryl J. Mar, Connie J. Zhou, Jeoung-Sook Shin, Allan I. Basbaum, K. Mark Ansel
Journal: Science Immunology (2023)

Despite robust literature associating IL-31 with pruritic inflammatory skin diseases, its influence on cutaneous inflammation and the interplay between inflammatory and neurosensory pathways remain unmapped. Here, we examined the consequences of disrupting
Abstract P2140: Orally Delivered Modified Citrus Pectin Attenuates Aortic Dissection Development By Regulating Macrophage Pyroptosis Via Ierruption Of Galectin-3 And Toll-like Receptor 4 Interaction
Authors: Hsin-Ying Lu, Chun-Che Shih
Journal: Circulation Research (2023)

Background: Aortic dissection (AD) is a lethal vascular disease caused by the formation of hematoma in the middle layer of the aortic wall. Inflammation and oxidative stress play important roles in the development of AD. Galectin-3 (Gal-3) is a 26-kDa lectin recognized to regulate many aspects of inflammatory cell behavior. Modified citrus pectin (MCP) is a pH-modified form of the dietary soluble citrus peel fiber known as pectin. It is abundant in β-galactose, which allows it to bind to Gal-3, and is recommended as a therapeutic agent for immune support, cancer, toxicity, and fibrotic diseases. The aim of this study was to explore the effect of MCP on AD and its potential mechanism involved. Methods and Results: MCP (100mg/kg) was orally administrated once every two days to retard the development of 3-aminopropionitrile fumarate/angiotensin II-induced AD animal models. In vivo, AD aorta presented an increase in Gal-3 levels that were accompanied by an increase in macrophage. Treatment with MCP decreased the incidence and mortality of AD by reducing inflammatory cell infiltration to the aorta; it downregulated the gene expression of inflammation and pyroptosis, such as IL-6, TNF-α, NLRP3, caspase-1, and IL-1β. In vitro, MCP could inhibit macrophage pyroptosis in H 2 O 2 -stimulated Raw264.7 cells. Additionally, Gal-3 is directly bound to TLR4 in H 2 O 2 -induced macrophages but MCP almost completely disrupted their interaction and suppressed activation of NF-KB by co-immunoprecipitation assays. Conclusions: Gal-3 could be a new molecular mechanism associated with AD disease, implying the use of MCP as a promising therapeutic strategy to prevent AD development.
Abstract P1132: Mettl3 Induced Fibronectin M6a Mrna Methylation Facilitates Cardiac Fibrosis Following Myocardial Ischemia
Authors: Roshan K Dutta, Prabhat Ranjan, Karen Colin, Vasundhara Pathak, qinkun zhang, Hind Lal, Suresh K Verma
Journal: Circulation Research (2023)

Objective: Cardiac fibrosis is one of the most warranted cardiac impairments which ultimately leads to heart failure. N6-methyladenosine (m6A) is an abundant and conserved chemical modification in eukaryotic mRNA and is associated with mRNA metabolism. Recently, we showed that m6A mRNA methylation regulates the angiogenic potential of the endothelial cells following ischemic injury. However, the role of m6A mRNA methylation in cardiac fibrosis following ischemic injury is still elusive and needs improvement in treatment strategy. Methods: First we analyzed the available data set for the fibrosis-regulating targets in Sham and MI hearts. Further, we studied methylation patterns in vivo by inhibiting methylation in MI mice using STM2457. Then we assessed cardiac function using echocardiography and harvested tissue samples for further biochemical analysis. We also performed in vitro experiment to investigate the expression pattern of the screened gene (Fibronectin) in hypoxic cardiac fibroblast as an ischemic model. We also performed an Actinomycin D assay to check the role of methylation on FN mRNA stability. Fibrosis and other phenotypic statuses were studied using several molecular techniques including ICC/IHC. Finally, siMETTL3 was used to study rescue experiments. Results: We have shown upregulated FN expression post-MI, and also several methylation sites on FN mRNA in-silico. Histological and biochemical analysis showed increased fibrosis and m6A mRNA methylation in mice post-MI. Hypoxic stress in fibroblast induces mRNA methylation, which leads to FN mRNA stabilization and deposition of FN at the scar site by activated fibroblast. In contrast, METTL3 inhibition using STM 2457 significantly improved cardiac function. METTL3 inhibition significantly reduced FN mRNA methylation and FN expression, and ultimately reduced cardiac fibrosis. Conclusion: We observed that increased FN mRNA (m6A) methylation enhanced cardiac fibrosis following MI. Inhibition of mRNA methylation using STM2457 in in-vivo, and siRNA in-vitro reduced hypoxia-induced FN deposition and fibrosis, which suggests STM2457 could be a potential therapeutic molecule either alone or in combination with current regimens to curb methylation-induced cardiac fibrosis.
Abstract P1003: Expression Of Circulating Atherosclerosis-associated Micrornas In Pre- And Post-menopausal Obese Women: Response To Physical Exercise
Authors: Debora S Faffe, Diego Costa-dos-Santos, Bianca C Cabral, Thayane Bottaro, Rosane Silva, Turan P Urmenyi
Journal: Circulation Research (2023)

Atherosclerosis is the basic mechanism of cardiovascular disease, a major cause of mortality. It involves the interaction of environmental factors, such as obesity, and genetics, while exercise is a major risk modifier. Despite its higher prevalence in men, women have a worse outcome; however, they are underrepresented in clinical trials. MicroRNAs (miRs) are gene expression regulators of special interest as potential risk markers for complex diseases. We investigated the effect of physical exercise on the expression of circulating miRs in obese pre- and post-menopausal women. For this purpose, we analyzed serum from six women before and after performing a physical exercise protocol (3 x/week for 16 weeks). Samples were selected from women with extreme responses to the exercise protocol. The miRs were extracted using miRNeasy Serum/Plasma Kit and sequenced by mass sequencing on the Ion Torrent PGM platform. Data were analyzed using the CLC Genomics Workbench software. The differently expressed miRs were submitted to in silico analysis to determine the computational prediction of gene targets with the Mirnet tool (version 2.0). Then, the gene ontology of predicted target genes was verified using EnrichR. Altogether, five miRs with increased expression were identified for the menopausal group compared to the non-menopausal group before physical exercise (miR-199a, -222, -186, -4454, and 126). In the non-menopausal group, we identified one miR with increased expression (miR-122) and 4 with reduced expression (miR-29c, Let-7b, -339, and -98) after the exercise protocol. The menopause group showed an increase of 5 miRs (miR-15b, -19a, -107, -103a, 17) and a reduction of 4 (miR-423, -148a, -Let-7i, and -338) induced by exercise. Gene ontology analysis identified several pathways in the atherosclerosis process modulated by physical exercise. Our results showed that exercise induces the expression of circulating miRs that potentially regulates target genes involved in atherosclerosis physiopathology, inflammatory response, oxidative stress, and obesity. The pathways modulated by exercise differ among pre- and post-menopausal obese women, thus potentially impacting the approach of atherosclerosis in women.
Abstract P1111: Dysfunctional SCARNAs And Failed Pseudouridylation Result In Irregulation Of Cardiac Genes In Noonan Syndrome Patient-derived Induced Cardiomyocytes
Authors: Vinoth Sigamani, Selene G Perales, SHEEJA RAJASINGH, Hemanathan Vembuli, Rahul Pushparaj, Johnson Rajasingh
Journal: Circulation Research (2023)

Background: Small Cajal body associated RNAs (scaRNAs) can control alternative splicing and the maturation of mRNAs by regulating the pseudouridylation (PsU) of small nuclear RNAs (snRNAs), which are involved in the formation of the spliceosome complex, via RNA-dependent mechanism. Failure of snRNA PsU results in dysregulated mRNA splicing and maturation which causes congenital heart defects. In this study, we aim to find the importance of snRNAs PsU in Noonan syndrome (NS) patients-derived induced pluripotent stem cell-derived cardiomyocytes (NS-iCM) when compared to normal skin fibroblast iCM (SF-iCM). Hypothesis: We hypothesize that snRNAs PsU by scaRNAs will have a significant role in the development of cardiomyocytes in NS patients. Methods and Results: We generated iCMs from SF-iPSCs and NS patient-derived NS-iPSCs. The qRT-PCR analysis showed a significantly lower expression of scaRNA6, scaRNA20, and scaRNA28 in NS-iCMs when compared with control SF-iCMs (Fig. A). The PsU of snRNA U12 was quantified by RNA Immunoprecipitation (RIP) using the Pseudouridine (Ψ)-specific antibody and mouse IgGas a negative control. The data showed that snRNA U12 was significantly reduced in the NS-iCM when compared with negative IgG (Fig. B). Furthermore, the PsU modification was quantified by using the 1-cyclohexyl- (2-morpholinoethyl) carbodiimide metho-p-toluene sulfonate (CMCT) method. Our data showed that relative Ψ units were significantly reduced in the NS-iCMs when compared with normal SF-iCMs (Fig. C). Conclusion: Our results indicate that snRNAs PsU by scaRNAs were dysfunctional in NS-iCMCs, which may result in cardiac defects in NS patients.
Abstract P2141: Effect Of Anakinra On Peak Oxygen Consumption In Patients With Heart Failure With Reduced Ejection Fraction: A Meta-analysis
Authors: Manisha Jain, Dakshin Meenashi Sundaram, Kamran Mahfooz, Sai Pranathi Gaddipati, Subhav Ramnani, Kaunain Baig, Gurmehak Kaur, Thulasi Ram Gudi, Advait Vasavada
Journal: Circulation Research (2023)

Background: Peak oxygen consumption(VO2) evaluates an individual's aerobic fitness level, and provides information on overall health and fitness. Prior studies on anakinra in heart failure have not evaluated VO2 specifically in the subgroup of heart failure with reduced ejection fraction(HFrEF). Our aim was to evaluate the effect of this drug in this population. Methods: We searched five databases: Embase, MEDLINE, Cochrane, Scopus, and PubMed, for RCTs evaluating the effects of Anakinra against a placebo in HFrEF. Meta-analysis was performed using RevMan 5.4 and a random-effects model was used for the analysis. Three RCTs were identified Results: The analysis of the Anakinra effect on VO2 in patients with HFrEF was determined using 3 RCTs. Most studied its effect after 2 weeks. Compared to placebo/standard treatment, anakinra was associated with a greater change in peak VO2 from baseline VO2. However, the difference between Anakinra and placebo in peak VO2 changes was not statistically significant (MD 0.07, 95% CI -0.41 to 0.56; I2 = 43%) with an overall test effect of Z = 0.29 at p = 0.77. The VE/VCO2 slope determined the effect of Anakinra on ventilatory efficiency in HF patients. Among the 3 RCTs that evaluated VE/VCO2 slope, no difference was depicted between the Anakinra treatment relative to placebo. Thus, the statistical difference was insignificant between the two groups (MD 0.70, 95% CI -0.06 to 1.46; I2 = 0%) at p = 0.07. Conclusion: Anakinra was ineffective in improving VO2 in HFrEF. Future prospective studies with longer duration of treatment and measuring performance monitoring outcomes are needed to understand the effect of this drug for such outcomes.
Abstract P2144: Irisin, An Exercise-induced Myokine, Exhibits Protective Effects In Glucocorticoid-induced Cardiac Muscle Dysfunctions
Authors: Christina Y Sheng, Young Hoon Son, Sung J Park
Journal: Circulation Research (2023)

Myocardial infarction caused by pharmacological substances, such as anti-inflammatory drugs, is a serious adverse drug effect in the cardiovascular system that often causes heart failure. Dexamethasone (DEX), a synthetic glucocorticoid, is commonly used as potent anti-inflammatory and immunosuppressive drugs, but is classified as one of the prime suspects of drug-induced acute myocardial infarction. High dose of DEX increased oxidative stress of the heart, induced myocardial degeneration and cardiomyocyte apoptosis and impaired cardiac contraction. Thus, therapeutic approaches are required to alleviate glucocorticoids-induced cardiotoxicity and prevent DEX-mediated cardiac complications. Exercise-induced secretion of irisin showed the beneficial effects against cardiovascular diseases on energy metabolism, anti-oxidant effects, and decreased inflammation and apoptosis by promoting mitochondria biogenesis, decreasing oxidative stress and inflammatory responses, and regulating intracellular calcium signaling. In this study, we investigate the endocrine effects of muscle-secreted irisin against DEX-induced cardiotoxicity. We engineered anisotropic human induced-pluripotent stem cell-derived cardiomyocyte tissues and designed three experimental groups: control, dex treatment, and dex plus irisin treatment. We then analyze the tissues with qPCR, immunostaining (muscle atrophy markers), contractility assay, and oxygen consumption assay to evaluate the protective effects of irisin on DEX-induced cardiac injury. Injured cardiac tissues showed systolic dysfunction by decreasing oxygen consumption, increasing muscle atrophy marker (MuRF-1), and significantly reducing systolic contractile force, but not diastolic stress. In contrast, these DEX-induced maladaptive responses was alleviated by irisin pretreatment by reducing proteolytic activity and muscle atrophy signaling pathways and promoting mitochondria biogenesis. In conclusion, our micro-physiological system showed the therapeutic effects of irisin against DEX-induced cardiotoxicity.